Piperidine derivatives and their use as modulators of chemokine receptor activity (especially ccr5)

ABSTRACT

Compounds of formula (I): compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).

The present invention relates to heterocyclic derivatives havingpharmaceutical activity, to processes for preparing such derivatives, topharmaceutical compositions comprising such derivatives and to the useof such derivatives as active therapeutic agents.

Pharmaceutically active piperidine derivatives are disclosed inPCT/SE01/01053, EP-A1-1013276, WO00/08013, WO99/38514 and WO99/04794.

Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract macrophages, T cells, eosinophils, basophils andneutrophils to sites of inflammation and also play a rôle in thematuration of cells of the immune system. Chemokines play an importantrôle in immune and inflammatory responses in various diseases anddisorders, including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Thesesmall secreted molecules are a growing superfamily of 8-14 kDa proteinscharacterised by a conserved four cysteine motif. The chemokinesuperfamily can be divided into two main groups exhibitingcharacteristic structural motifs, the Cys-X-Cys (C—X—C, or α) andCys-Cys (C—C, or β) families. These are distinguished on the basis of asingle amino acid insertion between the NH-proximal pair of cysteineresidues and sequence similarity.

The C—X—C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages,dendritic cells, microglia and other cell types. These detect andrespond to several chemokines, principally “regulated on activationnormal T-cel expressed and secreted” (RANTES), macrophage inflammatoryproteins (MIP) MIP-1α and MIP-1β and monocyte chemoattractant protein-2(MCP-2).

This results in the recruitment of cells of the immune system to sitesof disease. In many diseases it is the cells expressing CCR5 whichcontribute, directly or indirectly, to tissue damage. Consequently,inhibiting the recruitment of these cells is beneficial in a wide rangeof diseases.

CCR5 is also a co-receptor for HIV-1 and other viruses, allowing theseviruses to enter cells. Blocking the receptor with a CCR5 antagonist orinducing receptor internalisation with a CCR5 agonist protects cellsfrom viral infection.

The present invention provides a compound of formula (I):

wherein:

-   R¹ is phenyl {para-substituted by: halo, hydroxy, nitro,    S(O)_(k)(C₁₋₆alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₆ alkyl), S(O)₂N(C₁₋₆    alkyl)₂, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆    alkyl)₂, C(O)NH₂, C(O)NH(C₁₋₆ alkyl), C(O)N(C₁₋₆ alkyl)₂,    C(O)[N-linked heterocyclyl], CO₂H, CO₂(C₁₋₆ alkyl), NHC(O)(C₁₋₆    alkyl), NHC(O)O(C₁₋₆ alkyl), NHS(O)₂(C₁₋₆ alkyl), C(O)(C₁₋₆ alkyl),    CF₃, OCF₃, phenyl, heteroaryl, (C₁₋₄ alkyl)phenyl, (C₁₋₄    alkyl)heteroaryl, NHC(O)phenyl, NHC(O)heteroaryl, NHC(O)(C₁₋₄    alkyl)phenyl, NHC(O)(C₁₋₄ alkyl)heteroaryl, NHS(O)₂phenyl,    NHS(O)₂heteroaryl, NHS(O)₂(C₁₋₄ alkyl)phenyl, NHS(O)₂(C₁₋₄    alkyl)heteroaryl, NHC(O)NH(C₁₋₆ alkyl), NHC(O)NH(C₃₋₇ cycloalkyl),    NHC(O)NHphenyl, NHC(O)NHheteroaryl, NHC(O)NH(C₁₋₄ alkyl)phenyl or    NHC(O)NH(C₁₋₄ alkyl)heteroaryl; wherein the foregoing phenyl and    heteroaryl groups are optionally substituted by halo, hydroxy,    nitro, S(O)_(k)(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),    S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,    C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl),    NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or    OCF₃};-   R² is phenyl or heteroaryl, either of which is optionally    substituted by halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, S(O)_(n)(C₁₋₄ alkyl),    nitro, cyano or CF₃;-   R³ is hydrogen or C₁₋₄ alkyl;-   R⁴ is ethyl, allyl or cyclopropyl;-   R⁵ is hydrogen, halo, hydroxy, nitro, S(O)_(m)(C₁₋₄ alkyl),    S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄    alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂,    CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),    C(O)(C₁₋₄ alkyl), CF₃ or OCF₃;-   R⁶ is C₁₋₄ alkyl;-   k, m and n are, independently, 0, 1 or 2;-   or a pharmaceutically acceptable salt thereof or a solvate thereof;    provided that:    -   when R³ and R⁵ are both hydrogen, R⁴ is ethyl, R⁶ is        para-(S(O)₂CH₃) and R² is unsubstituted phenyl then R¹ is not        para-methoxy-phenyl, para-methyl-phenyl,        para-trifluoromethyl-phenyl or 3,4-dichlorophenyl;    -   when R³ and R⁵ are both hydrogen, R⁴ is ethyl, R⁶ is        para-(S(O)₂CH₃) and R² is unsubstituted phenyl, pyrid-2-yl or        pyrid-4-yl then R¹ is not para-chloro-phenyl; and,    -   when R³ and R⁵ are both hydrogen, R⁶ is para-(S(O)₂CH₃) and R²        is meta-chloro-phenyl, unsubstituted phenyl or thiophen-3-yl        then R¹ is not para-fluoro-phenyl.

Certain compounds of the present invention can exist in differentisomeric forms (such as enantiomers, diastereomers, geometric isomers ortautomers). The present invention covers all such isomers and mixturesthereof in all proportions.

Suitable salts include acid addition salts (adducts) such as ahydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate,or, additionally, formate. Acid addition salt is, for examplehydrochloride or formate.

The compounds of the invention may exist as solvates (such as hydrates)and the present invention covers all such solvates.

Alkyl groups and moieties are straight or branched chain and are, forexample, methyl (sometimes abbreviated to Me), ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl or tert-butyl.

Cycloalkyl is for example, cyclopropyl, cyclopentyl or cyclohexyl.

N-Linked heterocyclyl is a nitrogen-linked, non-aromatic 3, 4, 5 or 6membered ring optionally comprising one further heteroatom (selectedfrom the group comprising nitrogen, oxygen and sulphur). It is, forexample, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl or thiomorpholinyl.

Heteroaryl is an aromatic 5 or 6 membered ring, optionally fused to oneor more other rings, comprising at least one heteroatom selected fromthe group comprising nitrogen, oxygen and sulphur; or an N-oxidethereof, or an S-oxide or S-dioxide thereof. Heteroaryl is, for example,furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl,isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl,[1,2,4]-triazolyl, pyridinyl, pyrimidinyl, indolyl, benzo[b]furl (alsoknown as benzfuryl), benz[b]thienyl (also known as benzthienyl orbenzthiophenyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl,benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such asimidazo[1,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl,1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl),2,1,3-benzothiadiazolyl, benzofurazan (also known as2,1,3-benzoxadiazolyl), quinoxalinyl, a pyrazolopyridine (for example1H-pyrazolo[3,4-b]pyridinyl), quinolinyl, isoquinolinyl, anaphthyridinyl (for example [1,6]naphthyridinyl or [1,8]naphthyridinyl),a benzothiazinyl or dibenzothiophenyl (also known as dibenzothienyl); oran N-oxide thereof, or an S-oxide or S-dioxide thereof. Heteroaryl isespecially pyridyl, pyrimidinyl; indolyl or benzimidazolyl.

(C₁₋₄ Alkyl)phenyl is, for example, benzyl, 2-phenylethyl or1-phenyleth-1-yl. (C₁₋₄ Alkyl)heteroaryl is, for example, pyridylmethylor pyrimidinylmethyl. NHC(O)Heteroaryl is, for example, NHC(O)₂pyridyl.NHC(O)(C₁₋₄ Alkyl)phenyl is, for example, NHC(O)benzyl. NHC(O)₂(C₁₋₄Alkyl)heteroaryl is, for example, NHC(O)CH₂pyridyl. NHS(O)₂Heteroarylis, for example, NHS(O)₂pyridyl. NHS(b)₂(C₁₋₄ Alkyl)phenyl is, forexample, NHS(O)₂benzyl. NHS(O)₂(C₁₋₄ Alkyl)heteroaryl is, for example,NHS(O)₂CH₂pyridyl. NHC(O)NHheteroaryl is, for example, NHC(O)NHpyridyl.NHC(O)NH(C₁₋₄ Alkyl)phenyl is, for example, NHC(O)NHbenzyl.NHC(O)NH(C₁₋₄ Alkyl)heteroaryl is, for example, NHC(O)NHCH₂pyridyl.

In one aspect of the invention k, m and n are, independently, 0 or 2. Ina further aspect of the invention k, m and n are all 2.

In another aspect of the invention R¹ is phenyl {para-substituted by:halo, S(O)_(k)(C₁₋₆ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₆ alkyl), S(O)₂N(C₁₋₆alkyl)₂, cyano, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, CO₂(C₁₋₆ alkyl),NHC(O)(C₁₋₆ alkyl), NHC(O)O(C₁₋₆ alkyl), NHS(O)₂(C₁₋₄ alkyl),NHC(O)phenyl, NHC(O)heteroaryl, NHC(O)(C₁₋₄ alkyl)phenyl, NHC(O)(C₁₋₄alkyl)heteroaryl, NHS(O)₂phenyl, NHS(O)₂heteroaryl, NHS(O)₂(C₁₋₄alkyl)phenyl, NHS(O)₂(C₁₋₄ alkyl)heteroaryl, NHC(O)NH(C₁₋₆ alkyl),NHC(O)NH(C₃₋₇ cycloalkyl), NHC(O)NHphenyl, NHC(O)NHheteroaryl,NHC(O)NH(C₁₋₄ alkyl)phenyl or NHC(O)NH(C₁₋₄ alkyl)heteroaryl; whereinthe foregoing phenyl and heteroaryl groups are optionally substituted byhalo, hydroxy, nitro, S(O)_(k)(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃,[especially optionally substituted by halo]}. The variable k is 2.

In a further aspect of the invention R¹ is phenyl {para-substituted by:halo, cyano, CO₂(C₁₋₆ alkyl), NHC(O)(C₁₋₆ alkyl), NHS(O)₂(C₁₋₆ alkyl),NHC(O)phenyl, NHC(O)heteroaryl, NHC(O)(C₁₋₄ alkyl)phenyl, NHC(O)(C₁₋₄alkyl)heteroaryl, NHS(O)₂phenyl, NHS(O)₂heteroaryl, NHS(O)₂(C₁₋₄alkyl)phenyl or NHS(O)₂(C₁₋₄ alkyl)heteroaryl; wherein the foregoingphenyl and heteroaryl groups are optionally substituted by halo,hydroxy, nitro, S(O)_(k)(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alky),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃,[especially optionally substituted by halo]}. The variable k is 2.

In a still further aspect of the invention R¹ is phenyl{para-substituted by: halo, cyano, CO₂(C₁₋₆ alkyl), NHC(O)(C₁₋₆ alkyl),NHS(O)₂(C₁₋₆ alkyl), NHC(O)(C₁₋₄ alkyl)phenyl, NHC(O)(C₁₋₄alkyl)heteroaryl, NHS(O)₂(C₁₋₄ alkyl)phenyl or NHS(O)₂(C₁₋₄alkyl)heteroaryl; wherein the foregoing phenyl and heteroaryl groups areoptionally substituted by halo}.

In another aspect R¹ is phenyl para-substituted by S(O)_(k)(C₁₋₄ alkyl),wherein k is 0, 1 or 2, (for example SCH₃, S(O)CH₃ or S(O)₂CH₃),NHS(O)₂(C₁₋₄ alkyl) (for example NHS(O)₂CH₃) or NHC(O)(C₁₋₄ alkyl) (forexample NHC(O)CH₃). In yet another aspect R¹ is phenyl para-substitutedby S(O)₂(C₁₋₄ alkyl) (for example S(O)₂CH₃), NHS(O)₂(C₁₋₄ alkyl) (forexample NHS(O)₂CH₃) or NHC(O)(C₁₋₄ alkyl) (for example NHC(O)CH₃). In astill further aspect R¹ is phenyl para-substituted by S(O)₂(C₁₋₄ alkyl)(for example S(O)₂CH₃).

In a further aspect of the invention R² is phenyl or heteroaryl, eitherof which is optionally substituted in the ortho or meta position (thatis ortho or meta to the point of attachment of the R² ring to the therest of the structure of formula (I)) by halo, C₁₋₄ alkyl, C₁₋₄ alkoxy,S(O)_(n)(C₁₋₄ alkyl), nitro, cyano or CF₃.

In another aspect of the invention R² is phenyl or heteroaryl, either ofwhich is optionally substituted in the ortho or meta position (that isortho or meta relative to the position of attachment of that ring to thestructure of formula (I)) by halo, C₁₋₄ alkyl, C₁₋₄ alkoxy,S(O)_(n)(C₁₋₄ alkyl), nitro, cyano or CF₃; wherein n is 0, 1 or 2, forexample 0 or 2.

In yet another aspect R² is optionally substituted phenyl (especiallyoptionally substituted by halo (such as chloro or fluoro), cyano,methyl, ethyl, methoxy, ethoxy or CF₃). In one aspect said substitutionis on the ortho or meta position of the phenyl ring.

In a further aspect R² is optionally substituted phenyl (especiallyoptionally substituted by halo or CF₃). For example R² is3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl or 4-CF₃-phenyl.

In a still further aspect R² is phenyl, mono-fluorophenyl (for example3-fluorophenyl or 4-fluorophenyl), difluorophenyl (for example3,4-difluorophenyl or 3,5-dofluorophenyl), mono-chlorophenyl (forexample 3-chlorophenyl) or mono-(C₁₋₄ alkoxy)phenyl (for example4-methoxyphenyl). In a still further aspect R² is phenyl ormono-fluorophenyl (for example 3-fluorophenyl or 4-fluorophenyl).

In another aspect of the invention R³ is hydrogen or methyl. When R³ isC₁₋₄ alkyl (such as methyl) the carbon to which R³ is attached has, forexample, the R absolute configuration. In yet another aspect of theinvention R³ is hydrogen. In a further aspect of the invention R³ ismethyl.

In a still further aspect of the invention R⁴ is ethyl.

In another aspect of the invention R⁵ is hydrogen, halo, hydroxy, nitro,cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃ or OCF₃. In a further aspect R⁵ ishydrogen.

In a still further aspect of the invention R⁶ is methyl or ethyl (suchas methyl). A compound of the invention wherein R⁶ is methyl. A compoundof the invention wherein the S(O)₂R⁶ group of formula (I) is paradisposed to the remainer of the structure of formula (1), that is, it isas shown here:

In another aspect of the invention R⁶ is C₁₋₄ alkyl and wherein theS(O)₂R⁶ group of formula (I) is para disposed to the remainder of thestructure of formula (I).

In a still further aspect the present invention provides a compound offormula (Ia):

wherein R¹, R² and R³ are as defined above; provided that:

-   -   when R³ is hydrogen and R² is unsubstituted phenyl then R¹ is        not para-methoxy-phenyl, para-methyl-phenyl or        para-trifluoromethyl-phenyl;    -   when R³ is hydrogen and R² is unsubstituted phenyl, pyrid-2-yl        or pyrid-4-yl then R¹ is not para-chloro-phenyl;    -   when R³ is hydrogen and R² is unsubstituted phenyl then R¹ is        not 3,4-dichlorophenyl; and,    -   when R³ is hydrogen and R² is meta-chloro-phenyl, unsubstituted        phenyl or thiophen-3-yl then R¹ is not para-fluoro-phenyl.

The present invention further provides a compound of formula (I) or (Ia)wherein R¹ is phenyl para-substituted by S(O)₂(C₁₋₄ alkyl) (such asS(O)₂CH₃); R² is phenyl or mono-fluorophenyl (such as 3-fluorophenyl);and R³ is hydrogen or C₁₋₄ alkyl (such as methyl) (R³ is, for example,hydrogen); said compound being in free base form or in the form of ahydrochloride adduct.

The following compounds illustrate the invention. TABLE I Table Icomprises compounds of formula (Ia). (Ia)

Compound LCMS No. R¹ R² R³ Adduct *Chirality ^(†)Chirality (MH+) 14-Chlorophenyl Pyrid-3-yl H 554 2 4-Chlorophenyl Phenyl H (−)isomer^(#)553 3 4-Cyanophenyl Phenyl H 544 4 4-Methoxycarbonylphenyl Phenyl H 5775 4-(Morpholin-4-ylcarbonyl)phenyl Phenyl H 632 6 4-CarboxamidophenylPhenyl H 562 7 4-iso-propoxycarbonylphenyl Phenyl H 605 8 4-FluorophenylPhenyl H 9 4-Aminophenyl Phenyl H 534 104-tert-butyloxycarbonylaminophenyl Phenyl H 634 114-(Pyridin-2-ylacetylamino)phenyl Phenyl H 653 124-(Pyridin-3-ylacetylamino)phenyl Phenyl H 653 134-(Pyridin-4-ylacetylamino)phenyl Phenyl H 653 144-Phenylacetylaminophenyl Phenyl H 652 15 4-Butyrylaminophenyl Phenyl H604 16 4-Acetylaminophenyl Phenyl H 576 17 4-CyclohexylureidophenylPhenyl H 659 18 4-Phenylureidophenyl Phenyl H 653 194-Benzoylaminophenyl Phenyl H 638 20 4-(4-Chlorobenzoylamino)phenylPhenyl H 672 21 4-(2,2- Phenyl H 618 Dimethylpropionylamino)phenyl 224-Phenylmethanesulfonylamino- Phenyl H 688 phenyl 234-Ethanesulfonylaminophenyl Phenyl H 626 24 4-MethanesulfonylaminophenylPhenyl H 612 25 4-Phenylphenyl Phenyl H 595 26 4-Chlorophenyl3-Fluorophenyl H 571 27 4-Chlorophenyl 3-Fluorophenyl Methyl R isomer585 28 4-Benzenesulfonylaminophenyl Phenyl H 675 294-iso-propylsulfonylaminophenyl Phenyl H 30 4-Cyanophenyl Phenyl MethylR isomer 31 4-Cyanophenyl 3-Fluorophenyl Methyl R isomer 324-Methanesulfonylaminophenyl Phenyl Methyl R isomer 334-Methanesulfonylaminophenyl 3-Fluorophenyl Methyl R isomer 344-Acetylaminophenyl Phenyl Methyl R isomer 35 4-Acetylaminophenyl3-Fluorophenyl Methyl R isomer 36 4-Chlorophenyl Thien-2-yl H 374-Cyanophenyl Thien-2-yl H 38 4-Chlorophenyl Thiazol-4-yl H 394-Cyanophenyl Thiazol-4-yl H 40 4-Methanesulfonylphenyl Phenyl H 597 414-Methanethiophenyl Phenyl H 565 42 4-iso-propylaminocarboxy- Phenyl H619 aminophenyl 43 4-tert-butoxycarbonylaminophenyl 3-Fluorophenyl H 65244 4-Aminophenyl 3-Fluorophenyl H hydrochloride 552 454-Acetylaminophenyl 3-Fluorophenyl H 594 46 4-Methanesulfonylaminophenyl3-Fluorophenyl H 630 47 4-(4-Methanesulfonylbenzoylamino)-3-Fluorophenyl H hydrochloride 734 phenyl 484-(5-Methanesulfonylthien-2-yl- 3-Fluorophenyl H hydrochloride 740acetylamino)phenyl 49 4-Methanesulfonylammophenyl 3-Fluorophenyl Hhydrochloride (+)isomer^(†) 630 50 4-Methanesulfonylphenyl Phenyl Hhydrochloride S isomer 597 51 4-Methanesulfonylphenyl 3-Fluorophenyl Hhydrochloride R isomer 615 52 4-Methanesulfonylphenyl 4-Fluorophenyl Hhydrochloride S isomer 615 53 4-Methanesulfonylphenyl 3-Chlorophenyl Hhydrochloride R isomer 631 54 4-Methanesulfonylphenyl 3,4-DifluorophenylH hydrochloride R isomer 633 55 4-Methanesulfonylphenyl 4-MethoxyphenylH hydrochloride S isomer 627 56 4-Methanesulfonylphenyl3,5-Difluorophenyl H hydrochloride R isomer 633 574-Methanesulfonylphenyl Phenyl Methyl S isomer R isomer 584-Methanesulfonylphenyl 4-Fluorophenyl Methyl S isomer R isomer 594-Methanesulfonylphenyl 3,4-Difluorophenyl Methyl R isomer R isomer 604-Methanesulfonylphenyl 3,5-Difluorophenyl Methyl R isomer R isomer 614-Methanesulfonylphenyl 3-Fluorophenyl Methyl R isomer R isomer 624-Methanesulfonylphenyl 3-Trifluoromethylphenyl Methyl R isomer R isomer63 4-Methanesulfonylphenyl 3-Trifluoromethylphenyl H R isomer 644-Aminophenyl 3-Fluorophenyl H 65 4-(4-Methanesulfonylbenzoylamino)3-Fluorophenyl H phenyl 66 4-(5-Methanesulfonylthien-2-yl-3-Fluorophenyl H acetylamino)phenyl 67 4-Methanesulfonylaminophenyl3-Fluorophenyl H (+)isomer^(†) 68 4-Methanesulfonylphenyl Phenyl H Sisomer 69 4-Methanesulfonylphenyl 3-Fluorophenyl H R isomer 704-Methanesulfonylphenyl 4-Fluorophenyl H S isomer 714-Methanesulfonylphenyl 3-Chlorophenyl H R isomer 724-Methanesulfonylphenyl 3,4-Difluorophenyl H R isomer 734-Methanesulfonylphenyl 4-Methoxyphenyl H S isomer 744-Methanesulfonyiphenyl 3,5-Difluorophenyl H R isomer 754-Methanesulfinylpheny Phenyl H^(#)Compound separated from racemate using 10 micron Chiralcel OJ (250mm × 20 mm). As eluent comprises formic acid compound from column isformic acid adduct which was treated with base to yield free base,Compound No. 2. Estimated αD −7.29(CHCl₃, 589 nm, c = 0.425)^(†)Compound separated from racemate using 10 micron Chiralcel OJ (250mm × 20 mm). As eluent comprises formic acid compound from column isformic acid adduct which was treated with base to yield free base,Compound 67. Compound No. 67 used to form Compound 49. Estimated αD+5.85(CHCl₃, 589 nm, c = 2.00) for Compound No. 49.

In another aspect the present invention provides each individualcompound recited in Table I. In yet another aspect the present inventionprovides Compound No. 2 of Table L or a pharmaceutically acceptable saltthereof or a solvate thereof; Compound No. 50, 51, 67 or 68 of Table I,or a pharmaceutically acceptable salt thereof or a solvate thereof.

The compounds of the invention can be prepared as shown in the processeson pages marked Schemes 2 to 4 below, while Scheme 1 shows thepreparation of an intermediate used in Schemes 2 and 3. (In Schemes 1 to4 PG is a protecting Group; Ac is acetyl; Bn is benzyl, Bz is benzoyl;LDA is lithium diisopropylamide; and TMEDA isN,N,N′,N′-tetramethylethyenediamine. Suitable coupling agents includePyBrOP or HATU.)

A compound of the invention can be prepared by reductive amination of acompound of formula (II or (IIa):

with a compound of formula (III):

in the presence of NaBH(OAc)₃ (wherein Ac is C(O)CH₃) and acetic acid,in a suitable solvent (such as a C₁₋₆ aliphatic alcohol, for exampleethanol) at room temperature (for example 10-30° C.)

Alternatively, a compound of the invention can be prepared by coupling acompound of formula (IV) or (IVa):

with a compound of formula (V):

in the presence of a suitable coupling agent (for example PyBrOP orHATU) in the presence of a suitable base (such as a tertiary amine, forexample diisopropylethylamine) in a suitable solvent (for exampleN-methylpyrrolidinone or a chlorinated solvent, such as dichloromethane)at room temperature (for example 10-30° C.).

The starting materials for these preparative methods and Schemes areeither commercially available or can be prepared by literature methods,adapting literature methods or by following or adapting Methods hereindescribed.

In a further aspect the invention provides processes for preparing thecompounds of the invention. Many of the intermediates in the processesare novel and these are provided as further features of the invention.

The compounds of the invention have activity as pharmaceuticals, inparticular as modulators (such as agonists, partial agonists, inverseagonists or antagonists) of chemokine receptor (especially CCR5)activity, and may be used in the treatment of autoimmune, inflammatory,proliferative or hyperproliferative diseases, orimmunologically-mediated diseases (including rejection of transplantedorgans or tissues and Acquired Immunodeficiency Syndrome (AIDS)).

The compounds of the present invention are also of value in inhibitingthe entry of viruses (such as human immunodeficiency virus (HIV)) intotarget calls and, therefore, are of value in the prevention of infectionby viruses (such as HIV), the treatment of infection by viruses (such asHIV) and the prevention and/or treatment of acquired immune deficiencysyndrome (AIDS).

According to a further feature of the invention there is provided acompound of the invention, or a pharmaceutically acceptable salt thereofor a solvate thereof, for use in a method of treatment of a warm bloodedanimal (such as man) by therapy (including prophylaxis).

According to a further feature of the present invention there isprovided a method for modulating chemokine receptor activity (especiallyCCR5 receptor activity) in a warm blooded animal, such as man, in needof such treatment, which comprises administering to said animal aneffective amount of a compound of the present invention, or apharmaceutically acceptable salt thereof or a solvate thereof.

The present invention also provides the use of a compound of theinvention, or a pharmaceutically acceptable salt thereof or a solvatethereof, as a medicament, especially a medicament for the treatment oftransplant rejection, respiratory disease, psoriasis or rheumatoidarthritis (especially rheumatoid arthritis). [Respiratory disease is,for example, COPD, asthma {such as bronchial, allergic, intrinsic,extrinsic or dust asthma, particularly chronic or inveterate asthma (forexample late asthma or airways hyper-responsiveness)} or rhinitis{acute, allergic, atrophic rhinitis or chronic rhinitis includingrhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitissicca or rhinitis medicamentosa; membranous rhinitis including croupous,fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonalrhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis};and is particularly asthma or rhinitis].

In another aspect the present invention provides the use of a compoundof the invention, or a pharmaceutically acceptable salt thereof or asolvate thereof, in the manufacture of a medicament for use in therapy(for example modulating chemokine receptor activity (especially CCR5receptor activity (especially rheumatoid arthritis)) in a warm bloodedanimal, such as man).

The invention also provides a compound of the invention, or apharmaceutically acceptable salt thereof or a solvate thereof, for useas a medicament, especially a medicament for the treatment of rheumatoidarthritis.

In another aspect the present invention provides the use of a compoundof the invention, or a pharmaceutically acceptable salt thereof or asolvate thereof, in the manufacture of a medicament for use in therapy(for example modulating chemokine receptor activity (especially CCR5receptor activity (especially rheumatoid arthritis)) in a warm bloodedanimal, such as man).

The invention further provides the use of a compound of the invention,or a pharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behcet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, Lichen    planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, Alopecia greata or vernal conjunctivitis;    -   (4) (gastrointestinal tract) Coeliac disease, proctitis,        eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,        ulcerative colitis, irritable bowel disease or food-related        allergies which have effects remote from the gut (for example        migraine, rhinitis or eczema);    -   (5) (Allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin or cornea; or chronic graft versus host disease;        and/or    -   (6) (other tissues or diseases) Alzheimer's disease, multiple        sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome        (AIDS), Lupus disorders (such as lupus erythematosus or systemic        lupus), erythematosus, Hashimoto's thyroiditis, myasthenia        gravis, type I diabetes, nephrotic syndrome, eosinophilia        fascitis, hyper IgE syndrome, leprosy (such as lepromatous        leprosy), Peridontal disease, Sezary syndrome, idiopathic        thrombocytopenia pupura or disorders of the menstrual cycle; in        a warm blooded animal, such as man.

The present invention further provides a method of treating a chemokinemediated disease state (especially a CCR5 mediated disease state) in awarm blooded animal, such as man, which comprises administering to amammal in need of such treatment an effective amount of a compound ofthe invention, or a pharmaceutically acceptable salt thereof or solvatethereof.

In order to use a compound of the invention, or a pharmaceuticallyacceptable salt thereof or solvate thereof, for the therapeutictreatment of a warm blooded animal, such as man, in particularmodulating chemokine receptor (for example CCR5 receptor) activity, saidingredient is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the invention,or a pharmaceutically acceptable salt thereof or a solvate thereof(active ingredient), and a pharmaceutically acceptable adjuvant, diluentor carrier. In a further aspect the present invention provides a processfor the preparation of said composition which comprises mixing activeingredient with a pharmaceutically acceptable adjuvant, diluent orcarrier. Depending on the mode of administration, the pharmaceuticalcomposition will preferably comprise from 0.05 to 99% w (percent byweight), more preferably from 0.05 to 80% w, still more preferably from0.10 to 70% w, and even more preferably from 0.10 to 50% w, of activeingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by topical (such as to the lung and/or airways or to theskin), oral, rectal or parenteral administration. For these purposes thecompounds of this invention may be formulated by means known in the artinto the form of, for example, aerosols, dry powder formulations,tablets, capsules, syrups, powders, granules, aqueous or oily solutionsor suspensions, (lipid) emulsions, dispersible powders, suppositories,ointments, creams, drops and sterile injectable aqueous or oilysolutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 0.1 mg and 1 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous orintramuscular dose of 0.01 mgkg¹ to 100 mgkg⁻¹ of the compound,preferably in the range of 0.1 mgkg⁻¹ to 20 mgkg⁻¹ of this invention,the composition being administered 1 to 4 times per day. Theintravenous, subcutaneous and intramuscular dose may be given by meansof a bolus injection. Alternatively the intravenous dose may be given bycontinuous infusion over a period of time. Alternatively each patientwill receive a daily oral dose which is approximately equivalent to thedaily parenteral dose, the composition being administered 1 to 4 timesper day.

The following illustrate representative pharmaceutical dosage formscontaining the compound of the invention, or a pharmaceuticallyacceptable salt thereof or a solvent thereof (hereafter Compound X), fortherapeutic or prophylactic use in humans: (a) Tablet I mg/tabletCompound X 100 Lactose Ph.Eur. 179 Croscarmellose sodium 12.0Polyvinylpyrrolidone 6 Magnesium stearate 3.0

(b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur. 229 Croscarmellosesodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0

(c) Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur. 92Croscarmellose sodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate1.0

(d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur. 389 Croscarmellosesodium 100 Magnesium stearate 1.0

(e) Injection I (50 mg/ml) Compound X 5.0% w/v Isotonic aqueous solutionto 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethyleneglycol, polypropylene glycol, glycerol or ethanol or complexing agentssuch as hydroxy-propyl β-cyclodextrin may be used to aid formulation.

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

The invention will now be illustrated by the following non-limitingExamples in which, unless stated otherwise:

-   (i) temperatures are given in degrees Celsius (° C.); operations    were carried out at room or ambient temperature, that is, at a    temperature in the range of 18-25° C.;-   (ii) organic solutions were dried over anhydrous magnesium sulfate;    evaporation of solvent was carried out using a rotary evaporator    under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath    temperature of up to 60° C.;-   (iii) chromatography unless otherwise stated means flash    chromatography on silica gel; thin layer chromatography (TIC) was    carried out on silica gel plates; where a “Bond Elut” column is    referred to, this means a column containing 10 g or 20 g of silica    of 40 micron particle size, the silica being contained in a 60 ml    disposable syringe and supported by a porous disc, obtained from    Varian, Harbor City, Calif., USA under the name “Mega Bond Elut SI”.    Where an “Isolute™ SCX column” is referred to, this means a column    containing benzenesulphonic acid (non-endcapped) obtained from    International Sorbent Technology ltd., 1st House, Duffryn Industial    Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK. Where “Argonaut™    PS-tris-anine scavenger resin” is referred to, this means a    tris-2-aminoethyl)amine polystyrene resin obtained from Argonaut    Technologies Inc., 887 Industrial Road, Suite G, San Carlos, Cali.,    USA.-   (iv) in general, the course of reactions was followed by TLC and    reaction times are given for illustration only;-   (v) yields, when given, are for illustration only and are not    necessarily those which can be obtained by diligent process    development; preparations were repeated if more material was    required;-   (vi) when given, ¹H NMR data is quoted and is in the form of delta    values for major diagnostic protons, given in parts per million    (ppm) relative to tetramethylsilane (TMS) as an internal standard,    determined at 300 MHz using perdeuterio DMSO (CD₃SOCD₃) as the    solvent unless otherwise stated; coupling constants (J) are given in    Hz;-   (vii) chemical symbols have their usual meanings; SI units and    symbols are used;-   (viii) solvent ratios are given in percentage by volume;-   (ix) mass spectra (MS) were run with an electron energy of 70    electron volts in the chemical ionisation (APCI) mode using a direct    exposure probe; where indicated ionisation was effected by    electrospray (ES); where values for m/z are given, generally only    ions which indicate the parent mass are reported, and unless    otherwise stated the mass ion quoted is the positive mass ion    —CM+H)⁺;-   (x) LCMS characterisation was performed using a pair of Gilson 306    pumps with Gilson 233 XL sampler and Waters ZMD4000 mass    spectrometer. The LC comprised water symmetry 4.6×50 column C18 with    5 micron particle size. The eluents were: A, water with 0.05% formic    acid and B, acetonitrile with 0.05% formic acid. The eluent gradient    went from 95% A to 95% B in 6 minutes. Where indicated ionisation    was effected by electrospray (ES); where values for m/z are given,    generally only ions which indicate the parent mass are reported, and    unless otherwise stated the mass ion quoted is the positive mass    ion—(M+H)⁺ and

(xi) the following abbreviations are used: DMSO dimethyl sulfoxide; DMFN-dimethylformamide; DCM dichloromethane; THF tetrahydrofuran; DIPEAN,N-diisopropylethylamine; NMP N-methylpyrrolidinone; HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HBTUO-(7-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; Boc tert-butoxycarbonyl MeOH methanol; EtOHethanol; and EtOAc ethyl acetate.

EXAMPLE 1

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-phenylphenyl]propyl)-piperidin-4-yl-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 25 of Table I).

To a mixture ofN-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (Method A;500 mg, 1.54 mmol) and 3-phenyl-3-(4-phenylphenyl)propionaldehyde(Method B; 449 mg, 1.54 mmol) in DCM (10 mL) and ethanol (2 mL) wasadded one drop of acetic acid and the resulting mixture stirred at roomtemperature for 10 min. Sodium triacetoxyborohydride (327 mg, 1.54 mmol)was added and the resulting mixture was stirred at room temperature for2 h. The reaction mixture was washed with 2M aqueous sodium hydroxide(2×10 mL) and eluted through a 10 g SCX cartridge with DCM (2×10 mL),methanol (2×10 mL) and finally 0.5M ammonia in methanol (3×10 mL) toyield crude product which was purified by silica gel chromatography(eluent: DCM then ethyl acetate then 10% methanol in ethyl acetate) toyield the title compound (406 mg); NMR: 0.95-1.3 (m, 3H) 1.3-1.95 (m,8H) 2.2 (m, 3H) 2.8 (m, 2H) 3.15 (s, 3H) 3.8 (m, 2H) 4.05 (m, 3H)7.05-7.6 (m, 16H) 7.8 (d, 2H); MS: 595.

The procedure described in Example 1 can be repeated using differentaldehydes (such as 3-phenyl-3-(pyridin-2-yl)propionaldehyde (Method G),3-(4-chlorophenyl)-3-(3-fluorophenyl)propionaldehyde (Method I),(S)-3-phenyl-3-(4-methanesulfonylphenyl)propionaldehyde (Method N),(R)-3-(3-fluorophenyl)-3-(4-methanesulfonylphenyl)propionaldehdye(Method 0),(S)-3-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)propionaldehdye(Method P),(R)-3-(3-chlorophenyl)-3-(4-methanesulfonylphenyl)propionaldehdye(Method Q),(R)-3-(3,4-difluorophenyl)-3-(4-methanesulfonylphenyl)propionaldehdye(Method R),(S)-3-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)propionaldehdye(Method S), or(R)-3-(3,5-difluorophenyl)-3-(4-methanesulfonylphenyl)propionaldehdye(Method T)) in place of 3-phenyl-3-(4-phenylphenyl)propionaldehyde.

EXAMPLE 2

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-methoxycarbonyl-phenyl]propyl)-piperidin-4-yl)-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 4 of Table I).

This was prepared from3-phenyl-3-(4-methoxycarbonylphenyl)propionaldehyde (Method F) andN-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide using amethod similar to that used to prepareN-[1-(3-phenyl-3-[4-phenylphenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Example 1). NMR (CDCl₃): 1.1 and 1.2 (t; 3H), 1.5 (m, 1H), 1.8 (m, 2H),2.0 (br t, 2H), 2.2 (m, 4H), 2.9 (m, 2H), 3.0 (s, 3H), 3.3 (m, 2H), 3.8(m, 2H), 3.9 (s, 3H), 4.1 (m, 2H), 4.4 (m, 11), 7.2 (m, 7H), 7.5 (m, 2H)and 7.9 (m, 4H); MS: 577.

EXAMPLE 3

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-{morpholin-4-ylcarbonyl}phenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 5 of Table I).

To a solution ofN-[1-(3-phenyl-3-[4-carboxyphenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamidehydrochloride (Method H; 100 mg, 0.16 mmol) in DCM (4 mL) was addedoxalyl chloride (0.05 mL) and the resulting mixture was stirred at roomtemperature for 3 h. The mixture was cooled to 0° C. and a solution ofmorpholine in DCM was added dropwise until a pH of 9 was achieved. Thereaction mixture was washed with water and brine, dried (MgSO₄) andevaporated. The residue was purified by silica gel chromatography(eluent: 2% ammonia/10% methanol in DCM) giving the title compound (34mg); NMR (CDCl₃): 1.1 and 1.2 (t, 3H), 1.4 (m, 1H), 1.6 (m, 21), 1.8 (m,2H), 2.0 (m, 2H), 2.2 (m, 4H), 2.9 (m, 2H), 3.0 (s, 3H), 3.3 (q, 2H),3.6 (br m, 7H), 3.8 (m, 2H), 4.0 (m, 1H), 4.4 (m, 1H), 7.2 (m, 9H), 7.5(m, 2H) and 7.9 (d, 2H); MS: 632.

EXAMPLE 4

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-carboxamidophenyl]-3-propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 6 of Table I).

To a solution ofN-[1-(3-phenyl-3-[4-carboxyphenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamidehydrochloride (150 mg, 0.25 mmol) in DCM (4 mL) was added oxalylchloride (0.022 mL, 0.25 mmol) and the resulting mixture was stirred atroom temperature for 18 h. A solution of ammonia in methanol (10 mL) wasadded and the resulting mixture was stirred at room temperature for 2 h.The reaction mixture was washed with water and evaporated. The residuewas purified by silica gel chromatography (eluent: 1% ammonia/10%methanol in DCM) giving the title compound (23 mg); NMR (CDCl₃): 1.1 and1.2 (t, 3H), 1.5 (m, 2H), 1.6 (m, 1H), 1.8 (m, 2H), 2.0 (m, 2H), 2.2 (m,4H), 2.9 (m, 2H), 3.0 (s, 3M), 3.3 (q, 2H), 3.8 (m, 2H), 4.0 (m, 2H),4.4 (m, 1H), 7.2 (in, 7H), 7.4 (m, 2H), 7.7 (m, 2H) and 7.9. (d, 2H);MS: 562.

EXAMPLE 5

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-isopropoxycarbonyl-phenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamidehydrochloride (Compound No. 7 of Table I).

To a suspension ofN-(1-(3-phenyl-3-[4-carboxyphenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamidehydrochloride (40 mg, 0.07 mmol) in 2-propanol (4 mL) was added thionylchloride (3 drops). The resulting mixture was heated to reflux for 18 h,allowed to cool and evaporated. The residue was triturated with diethylether to give the title compound (31 mg); NMR: 1.0 and 1.1 (t, 3H), 1.3(t, 3H), 1.7 (m, 2H), 2.2 (m, 2H), 2.8 (m, 2M), 3.0 (m, 2H), 3.2 (s,3H), 3.3 (m, 4H), 3.5 (m, 2H), 3.8 (m, 2H), 4.0 and 4.2 (m, 1H), 4.1 (m,1H), 7.2 (m, 5H), 7.5 (br d, 4H) and 7.8 (br t, 4H); MS: 605.

EXAMPLE 6

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-cyanophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 3 of Table I).

To a mixture ofN-[1-(3-phenyl-3-[4-carboxamidophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Example 4; 0.33 mmol) in dioxane (5 mL) and pyridine (0.05 mL, 0.6mmol) at 0° C. was added trifluoroacetic anhydride (0.1 mL, 0.66 mmol)and the resulting mixture stirred at room temperature for 1 h. Thereaction mixture was washed with water and brine, dried (MgSO₄) andevaporated. The residue was purified by eluting through an SCX cartridgewith methanol then 2M ammonia in methanol to yield the title compound(27 mg); NMR (CDCl₃): 1.1 and 1.3 (t, 3H), 1.5 (m, 1H), 1.7 (m, 2H), 1.8(m, 2H), 2.0 (m, 1H), 2.2 (m, 4H), 2.9 (m, 2H), 3.0 (s, 3H), 3.3 (q,2H), 3.8 (m, 2H), 4.0 (m, 11H), 4.4 (m, 1H), 7.2 (m, 7H), 7.4 (m, 2H),7.6 (m, 2H) and 7.9 (d, 21); MS: 544.

EXAMPLE 7

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 9 of Table I).

N-[1-(3-Phenyl-3-[4-Boc-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Example 8; 6 g, 9.5 mmol) was dissolved in trifluoroacetic acid (25 mL)and the resulting mixture was stirred at room temperature for 2 h. Themixture was evaporated and the residue dissolved in 2M aqueous sodiumhydroxide (50 mL) and DCM (50 mL). The aqueous phase was extracted withDCM (3×25 mL) and the combined organic phases dried (MgSO₄) then elutedthrough a 50 g SCX cartridge with DCM (3×25 mL), methanol (3×25 mL) and1M ammonia in methanol (5×25 mL) to give the title compound (4.5 g); MS:534.

EXAMPLE 8

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-Boc-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 10 of Table I).

This was prepared from 3-phenyl-3-(4-Boc-aminophenyl)propionaldehyde(Method C) andN-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide using amethod similar to that used to prepareN-[1-(3-phenyl-3-[4-phenylphenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Example 1).

EXAMPLE 9

This Example illustrates the preparation ofN-[1-(3-phenyl-3-(4-pyridin-2-ylacetylaminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 11 of Table I).

To a solution of 2-pyridylacetic acid hydrochloride (81 mg, 4.7 mmol) inDCM (10 mL) was added triethylamine (47 mg, 4.7 mmol) and carbonyldiimidazole (75 mg, 4.7 mmol). The resulting mixture was stirred at roomtemperature for 4 h.N-[1-(3-Phenyl-3-[4-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(250 mg, 4.7 mmol) was added and the resulting mixture was stirred atroom temperature for 18 h. Isocyanate scavenger resin (0.3 g) was addedand the resulting mixture was stirred at room temperature for 2 h beforefiltration and washing with 2M aqueous sodium hydroxide (10 mL). Thefiltrate was extracted with DCM and extracts dried and evaporated togive the title compound (184 mg); MS: 653.

The procedure described in Example 9 can be repeated using differentcarboxylic acids (such as 3-pyridylacetic acid hydrochloride or4-pyridylacetic acid hydrochloride) in place of 2-pyridylacetic acidhydrochloride.

EXAMPLE 10

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-phenylacetylaminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 14 of Table I).

To a mixture ofN-[1-(3-phenyl-3-[4-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(250 mg, 4.7 mmol) and triethylamine (47 mg, 4.7 mmol) in DCM (10 mL)was added phenylacetyl chloride (72 mg, 4.7 mmol) and the resultingmixture was stirred at room temperature for 18 h. Trisamine scavengerresin (100 mg) was added and the resulting mixture was stirred at roomtemperature for 2 h before filtration. The filtrate was washed withsaturated aqueous sodium bicarbonate solution (10 mL), dried and elutedthrough a 10 g SCX cartridge with DCM (4×10 mL), methanol (4×10 mL) and1M ammonia in methanol (4×10 mL) to give the title compound (202 mg);MS: 652.

The procedure described in Example 10 can be repeated using differentcarbonyl chlorides (such as benzoyl chloride, 4-chlorobenzoyl chlorideor pivaloyl chloride) or sulfonyl chlorides (such as benzene sulfonylchloride or methane sulfonyl chloride) or isocyanates (such as phenylisocyanate or cyclohexyl isocyanate) in place of phenylacetic acid, anddifferent anilines (such asN-[1-(3-[3-fluorophenyl]-3-[4-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide)(Example 12) in place ofN-[1-(3-phenyl-3-[4-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide.When isocyanates are employed the triethylamine is omitted from thereaction.

EXAMPLE 11

This Example illustrates the preparation of(2R)-N-[1-(4-[4-chlorophenyl]-4-[3-fluorophenyl]but-2-yl)piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 27 of Table I).

To a mixture of(2R)-1-(4-[4-chlorophenyl]-4-[3-fluorophenyl]but-2-yl)-4-ethylaminopiperidine(Method K; 0.22 g, 0.56 mmol) and 4-methanesulfonylphenylacetic acid(0.33 g, 0.62 mmol) in DCM (10 mL) was added diisopropylcarbodiimide(0.1 mL, 0.62 mmol) and the resulting mixture was stirred at roomtemperature for 18 h before evaporation. The crude product was purifiedby eluting through a Bond Elut with DCM then 1% ammonia/10% methanol inDCM to give the title compound as a solid (0.36 g); NMR (CDCl₃): 0.9 (d,3H), 1.2 (t, 3H), 1.5 (m, 1H), 1.6 (m, 2H), 1.8 (m, 1H), 2.0 (m, 1H),2.2 (m, 2H), 2.4 (m, 1H), 2.5 (m, 1H), 2.7 (m, 1H), 3.0 (s, 3H), 3.3 (m,2H), 3.8 (m, 2H), 3.9 and 4.3 (m, 1H), 4.2 (m, 1H), 4.4 (m, 1H), 6.9 (m,3H), 7.2 (m, 5H), 7.5 (m, 2H) and 7.9 (d, 2H); MS: 585.

EXAMPLE 12

This Example illustrates the preparation ofN-[1-(3-[3-fluorophenyl]-3-[4-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamidehydrochloride (Compound No. 44 of Table I).

This was prepared fromN-[1-(3-[3-fluorophenyl]-3-[4-Boc-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Example 13) using a method similar to that used to prepareN-[1-(3-phenyl-3-[4-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Example 7); NMR: 1.0 and 1.15 (t, 3H), 1.7 (m, 2H), 2.3 (m, 2H), 2.8(m, 2H), 2.5 (m, 2H), 3.0 (m, 2H), 3.2 (s, 3H), 3.2 and 3.3 (m, 2H), 3.5(m, 2H), 3.7 and 4.1 (m, 1H), 3.8 and 3.9 (s, 2H), 4.35 (m, 1H), 7.0 (m,1H), 7.2 (m, 2H), 7.35 (m, 3H), 7.45 (m, 4H), 7.8 (d, 2H); MS: 552(MH+).

EXAMPLE 13

This Example illustrates the preparation ofN-[1-(3-[3-fluorophenyl]-3-[4-Boc-aminophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 43 of Table I).

This was prepared from3-(3-fluorophenyl)-3-(4-Boc-aminophenyl)propionaldehyde (Method L) andN-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide using amethod similar to that used to prepareN-[1-(3-phenyl-3-[4-phenylphenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Example 1); NMR (CDCl₃): 1.15 and 1.25 (t, 3H), 1.5 (s, 9H), 1.5 and1.65 (m, 2H), 1.95 (m, 2H), 2.0-2.3 (m, 6H), 2.9 and 3.0 (m, 2H), 3.0(s, 3H), 3.35 (ABq, 2H), 3.5 and 3.9 (m, 1H), 3.8 and 3.9 (s, 2H), 4.4(m, 1H), 6.55 (br s, 1H), 6.8-7.0 (m, 4H), 7.1-7.3 (m, 4H), 7.5 (m, 2H),7.9 (d, 2H); MS: 652 (MH+).

EXAMPLE 14

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-methanethiophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 41 of Table I).

This was prepared from 3-phenyl-3-(4-methanethiophenyl)propionaldehyde(Method M) andN-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide using amethod similar to that used to prepareN-[1-(3-phenyl-3-[4-phenylphenyl]propyl)-piperidin-4-yl]-N-ethyl-4methanesulfonylphenylacetamide (Example 1); NMR (CDCl₃): 1.15 and 1.25(t, 3H), 1.5 and 1.65 (m, 2H), 1.95 (m, 2H), 2.1-2.4 (m, 6H), 2.4 (s,3H), 2.95 and 3.1 (m, 2H), 3.0 (s, 3H), 3.35 (ABq, 2H), 3.5 and 3.9 (m,1H), 3.8 and 3.9 (s, 2H), 4.4 (m, 1H), 7.2 (m, 9H), 7.4 (m, 2H), 7.85(d, 2H); MS: 565 (MH+).

EXAMPLE 15

This Example illustrates the preparation ofN-[1-(3-phenyl-3-[4-methanesulfonylphenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(Compound No. 40 of Table I).

To a stirred solution ofN-[1-(3-phenyl-3-[4-methanethiophenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide(example 14, 0.33 g, 0.58 mmol) in DCM (50 mL) was added3-chloroperbenzoic acid (0.5 g, 2.92 mmol) and the resulting mixture wasstirred at room temperature for 2 h. The mixture was washed with water,dried (MgSO₄), pre-absorbed onto a Bond Elut, and eluted with a gradientof DCM to 1% ammonia/10% methanol in DCM giving a white foam (0.205 g);MS: 613. This was dissolved in DCM (5 mL) and the solution cooled to 0°C. To this solution was added a mixture prepared as follows: formic acid(0.03 mL, 0.75 mmol) was dropwise to acetic anhydride (0.06 mL, 0.625mmol) and the resulting mixture heated to 55° C. for 2 h then cooled.The resulting mixture was stirred at room temperature for 48 h. Waterwas added and the mixture basified with potassium carbonate to pH ofapproximately 10. The organic phase was dried (MgSO₄), pre-absorbed ontoa Bond Elut and eluted with a gradient of DCM to 1% ammonia/10% methanolin DCM giving the title compound (0.12 g); NMR (CDCl₃): 1.15 and 1.25(t, 3H), 1.5 and 1.65 (m, 2H), 1.6-2.0 (m, 4H), 2.25 (m, 4H), 2.9 and3.0 (m, 2H), 3.0 (s, 3H), 3.05 (s, 3H), 3.35 (ABq, 2H), 3.5 and 3.8 (m,1H), 3.8 and 4.1 (s, 2H), 4.4 (m, 1H), 7.2 (m, 5H), 7.45 (m, 4H), 7.8(d, 2H), 7.9 (d, 2H); MS: 597 (MH+).

Below is presented certain NMR data for some compounds of the invention.

(S)-N-[1-{3-phenyl-3-(4-methanesulfonylphenyl)propyl}-4-piperidinyl]-N-ethyl-4methanesulfonylphenylacetamide (Compound No. 50 of Table I).

NMR (CDCl₃): 1.15 and 1.25 (t, 3H), 1.5 and 1.65 (m, 2H), 1.6-2.0 (m,4H), 2.25 (m, 4H), 2.9 and 3.0 (m, 2H), 3.0 (s, 3H), 3.05 (s, 3H), 3.35(ABq, 2H), 3.5 and 3.8 (m, 1H), 3.8 and 4.1 (s, 2H), 4.4 (m, 1H), 7.2(m, 5H), 7.45 (m, 4H), 7.8 (d, 2H), 7.9 (d, 2H)

(S)-N-[1-{3-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)propyl}-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamidehydrochloride (Compound No. 52 of Table I).

NMR (d6-DMSO, 120° C.): 1.13 (t, 3H), 1.65 (m, 1H), 1.75 (m, 2H), 2.40(m, 1H), 2.61 (m, 2H), 2.9-3.1 (m, 4H), 3.14 (s, 6H), 3.3-3.4 (m, 4H),3.83 (s, 2H), 4.15 (m, 1H), 4.25 (dd, 1H), 7.10 (dd, 2H), 7.32 (dd, 2H),7.40 (d, 2H), 7.50 (d, 2H), 7.85 (m, 4H), 11.1 (br s, 1H).

(R)-N-[1-{3-(3-chlorophenyl)-3-(4-methanesulfonylphenyl)propyl}-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamidehydrochloride (Compound No. 53 of Table I).

NMR (d6-DMSO, 120° C.): 1.13 (t, 3H), 1.65 (m, 1H), 1.75 (m, 2H), 2.40(m, 1H), 2.61 (m, 2H), 2.9-3.1 (m, 4H), 3.14 (s, 3H), 3.3-3.4 (m, 7H),3.83 (s, 2H), 4.20 (m, 1H), 4.30 (dd, 1H), 7.25 (m, 1H), 7.32 (m, 2H),7.40 (s, 1H), 7.50 (d, 2H), 7.60 (d, 2H), 7.85 (m, 4H), 11.3 (br s, 1H).

(R)-N-[1-{3-(3,4-fluorophenyl)-3-(4-methanesulfonylphenyl)propyl}-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamidehydrochloride (Compound No. 54 of Table I).

NMR (d6-DMSO, 120° C.): 1.13 (t, 3H), 1.65 (m, 1H), 1.75 (m, 2H), 2.40(m, 1H), 2.61 (m, 2H), 2.9-3.1 (m, 4H), 3.14 (s, 6H), 3.3-3.4 (m, 4H),3.90 (s, 2H), 4.25 (m, 1H.), 4.35 (dd, 1H), 7.25 (m, 1H), 7.32 (dd, 1H),7.45 (dd, 1H), 7.52 (d, 2H), 7.63 (d, 2H), 7.85 (m, 4H), 11.3 (br s,1H).

(R)-N-[1-{3-(3,5-difluorophenyl)-3-(4-methanesulfonylphenyl)propyl}-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamidehydrochloride (Compound No. 56 of Table I).

NMR (d6-DMSO, 120° C.): 1.13 (t, 3H), 1.35 (m, 2H), 1.75 (m, 2H), 2.40(m, 2H), 2.61 (m, 2H), 2.9-3.1 (m, 4H), 3.14 (s, 6H), 3.35 (q, 2H), 3.45(m, 2H), 3.87 (s, 2H), 4.15 (m, 1H), 4.35 (dd, 1H), 6.95 (t, 1H), 7.10(d, 2H), 7.50 (d, 2H), 7.63 (d, 2H), 7.85 (m, 4H), 11.2 (br s, 1H).

Method A

N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide

Step 1: Preparation of 1-phenylmethyl-4-ethylaminopiperidineDihydrochloride

To a solution of 1-phenylmethyl-4-piperidone (25.0 g, 132 mmol) in THF(250 mL) was added ethylamine hydrochloride (12.0 g, 147 mol) andmethanol (50 mL) and the resulting mixture stirred at room temperaturefor 10 min. Sodium triacetoxyborohydride (40 g, 189 mmol) was addedportionwise and the resulting mixture stirred at room temperature for 1h. 2M Sodium hydroxide solution (250 mL) was added and the resultingmixture extracted with diethyl ether. The organic extracts were dried(K₂CO₃) and evaporated to give 1-phenylmethyl-4-ethylaminopiperidine asan oil. This was dissolved in ethanol (500 mL) and concentratedhydrochloric acid (20 mL) was added. The resulting crystals werecollected, washed with diethyl ether and dried giving the sub-titledcompound as a solid (38 g); NMR: (CDCl₃): 1.10 (t, 3H), 1.40 (m, 2H),1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H),3.75 (m, 1H), 7.2-7.4 (m, 5H); MS: 219 (MH+).

Step 2: Preparation ofN-(1-Phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide

To a solution of 1-phenylmethyl ethylaminopiperidine dihydrochloride(32.0 g, 110 mmol) in DCM (500 mL) was added N₃N-diisopropylethylamine(60 mL) with stirring to ensure complete dissolution.4-Methanesulfonylphenylacetic acid (25.0 g, 117 mmol),4-Dimethylaminopyridine (2.0 g) and dicyclohexylcarbodiimide (25.0 g,121 mmol) were added and the resulting mixture was stirred at roomtemperature for 20 h. The precipitate was removed by filtration and theresulting solution was washed successively with 2N aqueous HCl, waterand 1N aqueous NaOH, dried (MgSO₄) and evaporated. The residue waspurified by silica gel chromatography (eluent: 10% MeOH/ethyl acetate)to afford the sub-titled compound (35 g, 76%); NMR: 1.00 and 1.14 (t,3H), 1.45 and 1.70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3.18 (s,3H), 3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70and 4.10 (m, 1H), 7.2-7.3 (m, 5H), 7.48 (m, 2H), 7.82 (m, 2H); MS: 415(MH+).

Step 3: Preparation of the Title Compound

To a solution ofN-(1-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenyl-acetamide(34 g, 82 mmol) in ethanol (600 mL) was added ammonium formate (40 g).The mixture was purged with argon and 30% Pd on carbon (4.2 g) wasadded. The resulting mixture was stirred at reflux for 4 h, then allowedto cool and filtered through diatomaceous earth. The filtrate wasevaporated to give a thick oil which solidified on standing to yield thetitle compound (24.9 g, 94%); NMR: 1.02 and 1.15 (t, 3H), 1.4-1.6 (br m,4H), 2.45 (m, 2H), 2.93 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.32 (q, 2H),3.72 and 4.18 (m, 1H), 3.80 and 3.87 (s, 2H), 7.50 (m, 2H), 7.85 (m,2H); MS: 325 (MH+).

Method B

3-Phenyl-3-(4-phenylphenyl)propionaldehyde

Step 1: Preparation of Ethyl 3-phenyl-3-(4-phenylphenyl)acrylate

To a solution of triethylphosphonoacetate (6.7 g, 26 mmol) in THF (100mL) at 0° C. was added lithium bis(trimethylsilyl)amide (26 mL, 1M, 26mmol). The resulting mixture was stirred at 0° C. for 20 min.4-Benzoylbiphenyl (6.5 g, 26 mmol) was added and the resulting mixturewas stirred at room temperature for 48 h. The mixture was evaporated andthe residue dissolved in ethyl acetate (200 mL). The solution was washedwith 2M hydrochloric acid (2×100 mL), dried and evaporated giving thesub-titled compound (11 g).

Step 2: Preparation of Ethyl 3-phenyl-3-(4-phenylphenyl)propionoate

Ethyl 3-phenyl-3-(4-phenylphenyl)acrylate (11 g) was dissolved inethanol (200 mL) and the solution purged with argon. 20% Palladiumhydroxide (2 g) was added and the resulting mixture was stirred at roomtemperature under an atmosphere of hydrogen (balloon) for 72 h. Themixture was purged with argon, filtered and the filtrate evaporated. Thecrude product was purified by silica gel chromatography (eluent:isohexane then 25% ethyl acetate in isohexane) to give the sub-titledcompound (2.8 g).

Step 3: Preparation of 3-phenyl-3-(4-phenylphenyl)propan-1-ol

To a solution of ethyl 3-phenyl-3-(4-phenylphenyl)propionoate (2.8 g,8.48 mmol) in THF (30 mL) was added lithium aluminium hydride (8.48 mL,1M, 8.48 mmol) dropwise over 30 min. The resulting mixture was stirredat 0° C. for 1 h. 2M Aqueous sodium hydroxide (8 mL) was added dropwise.The mixture was filtered through Celite®, washing with ethyl acetate(3×25 mL). The filtrate and washings were combined and evaporated. Theresidue was dissolved in ethyl acetate (50 mL) and the resultingsolution washed with water (50 mL) and 2M hydrochloric acid (2×50 mL),dried and evaporated. The residue was purified by silica gelchromatography (eluent: isohexane then 40% ethyl acetate in isohexane)to give the sub-titled compound (1.3 g); NMR: 2.2 (q, 2H) 3.3 (q, 2H)4.1 (t, 1H) 4.25 (t, 1H) 7.1-7.6 (m, 14H).

Step 4: Preparation of the Title Compound

To a solution of 3-phenyl-3-(4-phenylphenyl)propan-1-ol (1.3 g, 3.3mmol) in DCM (50 mL) was added Dess-Martin periodinane (1.8 g, 4.4 mmol)and the resulting mixture was stirred at room temperature for 1.5 h. Themixture was washed with 2M aqueous sodium hydroxide (2×20 mL), dried andevaporated to give the title compound (1.3 g); NMR: 3.2 (d, 2H) 4.6 (t,1H) 7.1-7.7 (m, 14H) 9.7 (s, 1H).

Method C

3-Phenyl-3-(4-Boc-aminophenyl)propionaldehyde

This was prepared from 4-nitrobenzophenone using a similar sequence ofreactions to that used to prepare3-phenyl-3-(4-phenylphenyl)propanionaldehyde from 4-benzoylbiphenyl(Method B), except that an additional step was included between Steps 2and 3, namely treatment of ethyl 3-phenyl-3-(4-aminophenyl)propionatewith di-tert-butyldicarbonate to form ethyl3-phenyl-3-(4-Boc-aminophenyl)propionate.

Method D

E-(4R,5S)-1-(3-[4-Methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-one

To a stirred solution of 3-(4-methanesulfonylphenyl)acrylic acid (7.14g, 31.5 mmol) in DCM (10 mL) was added thionyl chloride (3 mL, 34.7mmol) dropwise and the resulting mixture was stirred at room temperaturefor 18 h. To this solution was added DIPEA (5.04 mL, 28.9 mmol) dropwiseat room temperature. The resulting solution was added to a stirredsolution of (4R, 5S)-3,4-dimethyl-5-phenyl-imidazolidin-2-one (5.0 g,26.3 mmol) in DCM (20 mL) and DIPEA (4.58 mL, 26.9 mmol) and theresulting mixture stirred at room temperature for 4 h. The mixture waswashed with water and brine, pre-absorbed onto a Bond Elut and elutedwith a gradient of isohexane to ethyl acetate giving the title compoundas a solid (7.61 g, 73%); NMR (CDCl₃): 0.84 (d, 3H), 2.89 (s, 3H), 3.04(s, 3H), 3.98 (m, 1H), 5.42 (d, 1H), 7.20 (m, 2H), 7.32 (m, 3H), 7.69(d, 1H), 7.74 (d, 2H), 7.93 (d, 2H), 8.31 (d, 1H); MS: 399 (MH+).

Method E

4-Methanethiobenzophenone

Step 1: Preparation of 1-(4-methanethiophenyl)phenylmethanol

To a solution of 4-methanethiobenzaldehyde (21 g, 138 mmol) in THF (200mL) at 0° C. was added phenyl lithium (84 mL, 152 mmol) dropwise. Theresulting mixture was stirred for 18 h with warming to room temperature.The mixture was washed with saturated aqueous ammonium chloride andbrine, dried (MgSO₄) and evaporated giving the sub-tided compound as asolid (30.16 g, 95%); NMR (CDCl₃): 2.28 (dt, 2H), 2.43 (s, 3H), 3.58 (t,2H), 4.10 (t, 1H), 7.23 (m, 5H).

Step 2: Preparation of Title Compound

To a solution of 1-(4-methanethiophenyl)phenylmethanol (30 g, 130 mmol)in DCM (400 mL) was added Dess-Martin periodinane (55 g, 143 mmol)portionwise at room temperature. The resulting mixture was stirred atroom temperature for 1 h, washed with 2M aqueous sodium hydroxide, dried(MgSO₄), pre-absorbed onto a silica column and eluted with a gradientelution (isohexane to DCM) to give the title compound as a solid (18.57g, 63%); NMR (CDCl₃): 2.53 (s, 3H), 7.29 (m, 2H), 7.48 (m, 2H), 7.58 (m,1H), 7.76 (m, 4H); MS: 229 (MH+).

Method F

3-Phenyl-3-(4-methoxycarbonylphenyl)propionaldehyde

Step 1: Preparation of diphenylmethane-4-carboxylic Acid Methyl Ester

To a suspension of diphenylmethane-4-carboxylic acid (10 g, 47 mmol) inmethanol (50 mL) was added thionyl chloride (0.34 mL, 4.7 mmol)dropwise. The resulting mixture was heated to reflux for 3 h thenallowed to cool. The mixture was evaporated and eluted through a plug ofsilica gel to give the sub-titled compound (9.7 g, 91%); NMR (CDCl₃):3.9 (s, 3H), 4.0 (s, 2H), 7.2 (m, 7H) and 8.0 (d, 2H).

Step 2: Preparation of 3-phenyl-3-(4-methoxycarbonylphenyl)but-1-ene

To a solution of diphenylmethane-4-carboxylic acid methyl ester (9.7 g,43 mmol) in THF (100 mL) under argon at −78° C. was added lithiumdiisopropylamide (23.5 mL, 2M, 47 mmol) dropwise and the resultingmixture was stirred at −78° C. for 1 h. Allyl bromide (1.85 mL, 21 mmol)was added and the resulting mixture was allowed to warm to roomtemperature over 18 h. The reaction mixture was washed with water andbrine, dried (MgSO₄) and evaporated. The residue was purified by silicagel chromatography (eluent: DCM) to give the subtitled compound as anoil (4.3 g); NMR (CDCl₃): 2.87 (dd, 2H), 3.91 (s, 3H), 4.12 (t, 1H),5.03 (m, 2H), 5.76 (m, 1H), 7.24 (m, 7H), 8.01 (d, 2H).

Step 3: Preparation of the Title Compound

A solution of 3-phenyl-3-(4-methoxycarbonylphenyl)but-1-ene (3.26 g,12.2 mmol) in methanol (100 mL) was purged with oxygen gas at −78° C.for 10 min. Ozone was bubbled through for 1 h until a blue colourpersisted. Dimethyl sulfide (1.8 mL, 25 mmol) was added and theresulting mixture was stirred at room temperature for 1 h thenevaporated to give the title compound which was used in the nextreaction without further purification.

Method G

3-Phenyl-3-(pyridin-2-yl)propionaldehyde

This was prepared from 2-benzylpyridine using a similar method to thatused to prepare 3-phenyl-3-(4-methoxycarbonylphenyl)propionaldehyde fromdiphenylmethane-4-carboxylic acid methyl ester (Method F).

Method H

N-[1-(3-phenyl-3-[4-carboxyphenyl]propyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamideHydrochloride

To a solution ofN-[1-(3-phenyl-3-[4-methoxycarbonylphenyl]propyl)-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide(Example 2; 2.36 g, 4.1 mmol) in methanol (40 mL) was added sodiumhydroxide (1.64 g, 41 mmol) and the resulting mixture was stirred atroom temperature for 3 days. The mixture was evaporated, the residue wastaken up in water and acidified to pH 1. The solid was collected andtriturated with methanol to give the title compound (0.73 g); NMR: 1.0and 1.1 (t, 3H), 1.4 (m, 2H), 1.6 (m, 2H), 1.8 (br t, 2H), 2.2 (m, 4H),2.8 (br t, 2H), 3.2 (s, 3H), 3.3 (m, 1H), 3.6 (m, 1H), 3.8 (d, 2H), 4.0(m, 2H), 7.1 (m, 1H), 7.3 (m, 4H), 7.5 (m, 4H) and 7.8 (d, 4H); MS: 563.

Method I

3-(4-Chlorophenyl)-3-(3-fluorophenyl)propionaldehyde

This was prepared from 4-chloro-3′-fluorobenzophenone (Method N) using asimilar sequence of reactions to that used to prepare3-phenyl-3-(4-phenylphenyl)propanionaldehyde from 4-benzoylbiphenyl(Method B), except that Step 2 was omitted.

Method J

4-Chloro-3′-fluorobenzophenone

Step 1: Preparation of 4-chlorophenyl-3-fluorophenylmethanol

To a solution of 3-fluorobenzaldehyde (5 g, 40 mmol) in THF (20 mL) wasadded 4-chlorophenylmagnesium bromide (44 mL, 1M in diethyl ether, 44mmol) dropwise and the resulting mixture was stirred at room temperaturefor 1 h. 2M Hydrochloric acid (10 mL) was added portionwise, the layersseparated and the organic phase evaporated. The residue was purified byBond Elut chromatography (eluent: isohexane then DCM) to give thesub-titled compound (5.1 g, 48%); NMR (CDCl₃): 2.2 (d, 1H), 5.8 (d, 1H),7.0 (m, 1H), 7.1 (m, 2H) and 7.3 (m, 5H).

Step 2: Preparation of the Title Compound

To a solution of 4-chlorophenyl-3-fluorophenylmethanol (1.55 g, 6.55mmol) in DCM (40 mL) was added Dess-Martin periodinane (3.06 g, 7.20mmol) and the resulting mixture was stirred at room temperature for 30min. The reaction mixture was washed with 2M aqueous sodium hydroxide,dried and evaporated. The residue was purified by Bond Elutchromatography (eluent: isohexane then DCM) to give the title compoundas a white solid (1.00 g, 64%); NMR (CDCl₃): 7.3 (m, 1H), 7.5 (m, 5H)and 7.8 (d, 2H).

Method K

(2R)-1-(4-[4-Chlorophenyl]-4-[3-fluorophenyl]but-2-yl)-4-ethylaminopiperidine

Step 1: Preparation of 4-chloro-3′-fluorodiphenylmethane

To a mixture of 4-chlorophenyl-3-fluorophenylmethanol (Step1 of MethodJ; 10 g, 38 mmol) and glacial acetic acid (150 mL) was added iodine (10g, 40 mmol) and hypophosphoric acid (30 mL, 50% aqueous, 285 mmol). Theresulting mixture was stirred at 60° C. for 16 h, allowed to cool anddiluted with water (300 mL). The mixture was extracted twice withisohexane and the combined extracts washed with saturated aqueous sodiumbicarbonate solution, dried (MgSO₄) and evaporated. The residue waspurified by silica gel chromatography (eluent: isohexane) to give thesub-titled compound (7.5 g); NMR (CDCl₃): 3.9 (s, 2H), 6.9 (m, 3H), 7.1(d, 2H) and 7.2 (m, 3H); MS: 220 (MH+).Step 2: Preparation of(1R)-N-tosyl-3-(4-chlorophenyl)-3-(3-fluorophenyl)-1-methylpropylamine

To a solution of 4-chloro-3′-fluorodiphenylmethane (7.0 g, 32 mmol) inTH (100 mL) at −10° C. was added lithium diisopropylamide (20 mL, 2M inhexane/TBF, 40 mmol) and the resulting mixture was stirred at −10° C.for 10 min. during which time a deep red colour was observed.(R)-2-Methyl-1-tosylaziridine (prepared from D-alaninol in two stepsusing literature procedures; 6.7 g, 32 mmol) was added and the resultingmixture was stirred with warming to room temperature for 1 h. Thereaction mixture was partitioned between saturated aqueous ammoniumchloride and diethyl ether, the combined organic phases were dried(MgSO₄) and evaporated to give the sub-titled compound as a solid (12g); NMR (CDCl₃): 1.0 (dd, 3H), 2.0 (m, 1H), 2.1 (m, 1H), 2.4 (s, 3H),3.1 (m, 1H), 4.0 (m, 1H), 4.6 (m, 1H), 6.8 (m, 1H), 6.9 (m, 1H), 7.2 (m,8H) and 7.6 (m, 2H).*Tetrahedron 44, 3919 (1988), Chem. Pharm. Bull. 25, 29 (1977).

Step 3: Preparation of(1R)-3-(4-chlorophenyl)-3-(3-fluorophenyl)-1-methylpropylamine

A mixture of(1R)-N-tosyl-3-(4-chlorophenyl)-3-(3-fluorophenyl)-1-methylpropylamine(10 g, 23 mmol) and 30% hydrobromic acid in glacial acetic acid (10 mL)was heated to 80° C. for 18 h, allowed to cool and evaporated. Theresidue was partitioned between diethyl ether and 2M aqueous sodiumhydroxide. The organic phase was evaporated and the residue purified bysilica gel chromatography (eluent: 2:1 ethyl acetate/methanol) to givethe sub-titled compound (2.2 g); NMR (CDCl₃): 1.4 (d, 3H), 2.2 (m, 2H),3.2 (br s, 2H), 4.3 (m, 1H) and 7.0 (br m, 8H): MS: 278 (MH+).Step 4: Preparation of(2R)-1-(4-[4-chlorophenyl]-4-[3-fluorophenyl]but-2-yl)-4-piperidone

To a solution of(1R)-3-(4-chlorophenyl)-3-(3-fluorophenyl)-1-methylpropylamine (2.0 g7.2 mmol) in ethanol (50 mL) was added a solution of potassium carbonate(1.5 g) in water (5 mL) and the resulting mixture heated to reflux withstirring. A solution of 1-methyl-1-ethyl-4-oxopiperidinium iodide (2.5g, 9.3 mmol) in water (15 mL) was added dropwise. The resulting mixturewas stirred at reflux for 10 min. then allowed to cool. The mixture wasconcentrated to about half the volume then extracted with DCM. Thecombined extracts were evaporated and the residue purified by silica gelchromatography (eluent: ethyl acetate) to give the sub-titled compound(700 mg); NMR: 0.9 (m, 3H), 2.0 (m, 1H), 2.2 (m, 1H), 2.3 (m, 4H), 2.4(m, 5H), 2.7 (m, 2H), 7.0 (m, 1H), 7.2 (m, 2H) and 7.3 (m, 5H).

Step 5: Preparation of the Title Compound

To a solution of(2R)-1-(4-[4-chlorophenyl]-4-[3-fluorophenyl]but-2-yl)-4-piperidone (400mg, 1.1 mmol) in ethanol (20 mL) was added ethylamine hydrochloride (200mg, 2.5 mmol) and the resulting mixture was stirred at room temperaturefor 10 min. until dissolved. Sodium triacetoxyborohydride (400 mg, 1.88mmol) was added and the resulting mixture was stirred at roomtemperature for 18 h. The reaction mixture was partitioned between 2Maqueous sodium hydroxide and diethyl ether. The organic phase was driedand evaporated and the residue purified by silica gel chromatography(eluent: 1% ammonia/10% methanol in DCM) to give the title compound (220mg); MS: 389 (MH+).

Method L

3-(3-Fluorophenyl)-3-(4-Boc-aminophenyl)propionaldehyde

This was prepared from 4-nitro-3′-fluorobenzophenone using a similarsequence of reactions to that used to prepare3-phenyl-3-(4-Boc-aminophenyl)propionaldehyde from 4-nitrobenzophenone(Method C).

Method M

3-Phenyl-3-(4-methanethiophenyl)propionaldehyde

This was prepared from 4-methanethiobenzophenone (Method E) using asimilar sequence of reactions to that used to prepare3-phenyl-3-(4-phenylphenyl)propanionaldehyde from 4-benzoylbiphenyl(Method B).

Method N

(S)-3-Phenyl-3-(4-methanesulfonylphenyl)propionaldehyde

Step 1: Preparation of (4R,5S)-1-[(S)-3-(4-methanesulfonyl-phenyl)-3-phenyl-propionyl]-3,4-dimethyl-5-phenyl-imidazolidin-2-one

To a mixture of copper (I) iodide (960 mg, 5.0 mmol) and THF (20 mL) wasadded N,N,N′,N′-tetramethylethylenediamine (0.83 mL, 5.5 mmol) and theresulting mixture was stirred at room temperature for 10 min. thencooled to −78° C. Phenylmagnesium bromide (5.0 mL, 1M in THF, 5.0 mmol)was added and the resulting mixture stirred at −78° C. for 15 min. Asolution of di-n-butylboron triflate (3.0 mL, 1M in diethyl ether, 3.0mmol) and (E)-(4R,5S)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-one(Method D, 1.0 g, 2.51 mmol) in THF (15 mL) was added and the resultingmixture was stirred whilst allowing to warm to room temperature for 18h. The reaction mixture was washed with saturated aqueous ammoniumchloride, water and brine, dried (MgSO₄) and evaporated. The residue waspurified by eluting through a 20 g Bond Elut with gradient of isohexaneto ethyl acetate giving the sub-titled compound (1.49 g, 100%); NMR(CDCl₃): 0.78 (d, 3H), 2.82 (s, 3H), 3.00 (s, 3H), 3.78 (dd, 1H), 3.80(m, 1H), 3.98 (dd, 1H), 4.72 (m, 1H), 5.19 (d, 1H), 6.99 (m, 2H), 7.22(m, 8H), 7.48 (d, 2H), 7.79 (d, 2H); MS: 477 (MH⁺).

Step 2: Preparation of(S)-3-phenyl-3-(4-methanesulfonylphenyl)propan-1-ol

To a solution of (4R,5S)-1-[(S)-3-(4-methanesulfonyl-phenyl)-3-phenyl-propionyl]-3,4-dimethyl-5-phenyl-imidazolidin-2-one(846 mg, 1.78 mmol) in THF (20 mL) at 0° C. was added lithium aluminiumhydride (3.6 mL, 1M in TBIF, 3.6 mmol) and the resulting mixture wasstirred for 15 min. The reaction was quenched by the addition of 2Maqueous sodium hydroxide. The phases were separated and the organicphase pre-absorbed onto a Bond Elut and eluted with a gradient ofisohexane to ethyl acetate giving the sub-titled compound as a whitesolid (285 mg, 55%); NMR (CDCl₃): 1.63 (br s, 1H), 2.33 (m, 2H), 3.00(s, 3H), 3.59 (t, 2H), 4.28 (t, 1H), 7.23 (m, 5H), 7.43 (d, 2H), 7.82(d, 2H).

Step 3: Preparation of the Title Compound

To a solution of (S)-3-phenyl-3-(4-methanesulfonylphenyl)propan-1-ol(244 mg, 0.84 mmol) in DCM (5 mL) was added Dess-Martin periodinane (392mg, 0.92 mmol) and the resulting mixture was stirred at room temperaturefor 1.5 h. The mixture was washed with 2M aqueous sodium hydroxide (2×10mL), dried and evaporated to give the title compound.

Method O

(R)-3-(3-fluorophenyl)-3-(4-methanesulfonylphenyl)propionaldehdye

This was prepared from (4R,5S)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-oneand 3-fluorophenylmagnesium bromide using a method similar to that usedto prepare (S)-3-phenyl-3-(4-methanesulfonyl-phenyl)propionaldehyde fromphenylmagnesium bromide (Method N); NMR (CDCl₃): 3.01 (s, 3H), 3.24 (d,2H), 4.73 (t, 1H), 6.91 (m, 2H), 6.99 (m, 1H), 7.28 (m, 2), 7.42 (d,2H), 7.87 (d, 2H), 9.76 (s, 1H).

Method P

(S)-3-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)propionaldehdye

This was prepared from (4R,5S)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-oneand 4-fluorophenylmagnesium bromide using a method similar to that usedto prepare (S)-3-phenyl-3-(4-methanesulfonyl-phenyl)propionaldehyde fromphenylmagnesium bromide (Method N).

Method Q

(R)-3-(3-chlorophenyl)-3-(4-methanesulfonylihenyl)propionaldehdye

This was prepared from (4R,5S)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-oneand 3-chlorophenylmagnesium bromide using a method similar to that usedto prepare (S)-3-phenyl-3-(4-methanesulfonyl-phenyl)propionaldehyde fromphenylmagnesium bromide (Method N).

Method R

(R)-3-(3,4-difluorophenyl)-3-(4-methanesulfonylphenyl)propionaldehdye

This was prepared from (4R,5S)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-oneand 3,4-difluorophenylmagnesium bromide using a method similar to thatused to prepare (S)-3-phenyl-3-(4-methanesulfonyl-phenyl)propionaldehydefrom phenylmagnesium bromide (Method N).

Method S

(S)-3-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)propionaldehdye

This was prepared from (4R,5S)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-oneand 4-methoxyphenylmagnesium bromide using a method similar to that usedto prepare (S)-3-phenyl-3-(4-methanesulfonyl-phenyl)propionaldehyde fromphenylmagnesium bromide (Method N).

Method T

(R)-3-(3,5-difluorophenyl)-3-(4-methanesulfonylhenyl)propionaldehdye

This was prepared from (4R,5S)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-oneand 3,5-difluorophenylmagnesium bromide using a method similar to thatused to prepare (S)-3-phenyl-3-(4-methanesulfonyl-phenyl)propionaldehydefrom phenylmagnesium bromide (Method N).

EXAMPLE 16

The ability of compounds to inhibit the binding of RANTES was assessedby an in vitro radioligand binding assay. Membranes were prepared fromChinese hamster ovary cells which expressed the recombinant human CCR5receptor. These membranes were incubated with 0.1 nM iodinated RANTES,scintillation proximity beads and various concentrations of thecompounds of the invention in 96-well plates. The amount of iodinatedRANTES bound to the receptor was determined by scintillation counting.Competition curves were obtained for compounds and the concentration ofcompound which displaced 50% of bound iodinated RANTES was calculated(IC₅₀). Preferred compounds of formula (1) have an IC₅₀ of less than 50μM.

EXAMPLE 17

The ability of compounds to inhibit the binding of MIP-1 α was assessedby an in vitro radioligand binding assay. Membranes were prepared fromChinese hamster ovary cells which expressed the recombinant human CCR5receptor. These membranes were incubated with 0.1 nM iodinated MIP-1α,scintillation proximity beads and various concentrations of thecompounds of the invention in 96-well plates. The amount of iodinatedMIP-1α bound to the receptor was determined by scintillation counting.Competition curves were obtained for compounds and the concentration ofcompound which displaced 50% of bound iodinated MIP-1α was calculated(IC₅₀). Preferred compounds of formula (1) have an IC₅₀ of less than 50μM.

Results from this test for certain compounds of the invention arepresented in Table II. In Table II the results are presented as Pic50values. A Pic50 value is the negative log (to base 10) of the IC₅₀result, so an IC50 of 1 μM. (that is 1×10⁻⁶ M) gives a Pic50 of 6. If acompound was tested more than once then the data below is an average ofthe probative tests results. TABLE II Compound No. Pic50 28 6.07 40 8.7741 7.93 42 7.88 43 7.05 44 6.98 45 8.44 46 8.04 47 7.46 48 6.51 49 8.2150 9.09 51 9.43 52 7.34 53 9 54 7.67 55 6.88 75 7.86

1. A compound of formula (I):

wherein: R¹ is phenyl {para-substituted by: halo, hydroxy, nitro,S(O)_(k)(C₁₋₆ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₆ alkyl), S(O)₂N(C₁₋₆alkyl)₂, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆alkyl)₂, C(O)NH₂, C(O)NH(C₁₋₆ alkyl), C(O)N(C₁₋₆ alkyl)₂, C(O)[N-linkedheterocyclyl], CO₂H, CO₂(C₁₋₆ alkyl), NHC(O)(C₁₋₆ alkyl), NHC(O)O(C₁₋₆alkyl), NHS(O)₂(C₁₋₆ alkyl), C(O)(C₁₋₆ alkyl), CF₃, OCF₃, phenyl,heteroaryl, (C₁₋₄ alkyl)phenyl, (C₁₋₄ alkyl)heteroaryl, NHC(O)phenyl,NHC(O)heteroaryl, NHC(O)(C₁₋₄ alkyl)phenyl, NHC(O)(C₁₋₄alkyl)heteroaryl, NHS(O)₂phenyl, NHS(O)₂heteroaryl, NHS(O)₂(C₁₋₄alkyl)phenyl, NHS(O)₂(C₁₋₄ alkyl)heteroaryl, NHC(O)NH(C₁₋₆ alkyl),NHC(O)NH(C₃₋₇ cycloalkyl), NHC(O)NHphenyl, NHC(O)NHheteroaryl,NHC(O)NH(C₁₋₄ alkyl)phenyl or NHC(O)NH(C₁₋₄ alkyl)heteroaryl; whereinthe foregoing phenyl and heteroaryl groups are optionally substituted byhalo, hydroxy, nitro, S(O)_(k)(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃};R² is phenyl or heteroaryl, either of which is optionally substituted byhalo, C₁₋₄ alkyl, C₁₋₄ alkoxy, S(O)_(n)(C₁₋₄ alkyl), nitro, cyano orCF₃; R³ is hydrogen or C₁₋₄ alkyl; R⁴ is ethyl, allyl or cyclopropyl; R⁵is hydrogen, halo, hydroxy, nitro, S(O)_(m)(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃or OCF₃; R⁶ is C₁₋₄ alkyl; k, m and n are, independently, 0, 1 or 2; ora pharmaceutically acceptable salt thereof or a solvate thereof;provided that: when R³ and R⁵ are both hydrogen, R⁴ is ethyl, R⁶ ispara-(S(O)₂CH₃) and R² is unsubstituted phenyl then R¹ is notpara-methoxy-phenyl, para-methyl-phenyl, para-trifluoromethyl-phenyl or3,4-dichlorophenyl; when R³ and R⁵ are both hydrogen, R⁴ is ethyl, R⁶ ispara-(S(O)₂CH₃) and R² is unsubstituted phenyl, pyrid-2-yl or pyrid-4-ylthen R¹ is not para-chloro-phenyl; and, when R³ and R⁵ are bothhydrogen, R⁶ is para-(S(O)₂CH₃) and R² is meta-chloro-phenyl,unsubstituted phenyl or thiophen-3-yl then R¹ is not para-fluoro-phenyl.2. A compound as claimed in claim 1 wherein R¹ is phenyl{para-substituted by: halo, S(O)_(k)(C₁₋₆ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₆alkyl), S(O)₂N(C₁₋₆ alkyl)₂, cyano, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂,CO₂(C₁₋₆ alkyl), NHC(O)(C₁₋₆ alkyl), NHC(O)O(C₁₋₆ alkyl), NHS(O)₂(C₁₋₆alkyl), NHC(O)phenyl, NHC(O)heteroaryl, NHC(O)(C₁₋₄ alkyl)phenyl,NHC(O)(C₁₋₄ alkyl)heteroaryl, NHS(O)₂phenyl, NHS(O)₂heteroaryl,NHS(O)₂(C₁₋₄ alkyl)phenyl, NHS(O)₂(C₁₋₄ alkyl)heteroaryl, NHC(O)NH(C₁₋₆alkyl), NHC(O)NH(C₃₋₇ cycloalkyl), NHC(O)NHphenyl, NHC(O)NHheteroaryl,NHC(O)NH(C₁₋₄ alkyl)phenyl or NHC(O)NH(C₁₋₄ alkyl)heteroaryl; whereinthe foregoing phenyl and heteroaryl groups are optionally substituted byhalo, hydroxy, nitro, S(O)_(k)(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃};and k is
 2. 3. A compound as claimed in claim 1 wherein R² is phenyl,mono-fluorophenyl, difluorophenyl, mono-chlorophenyl or mono-(C₁₋₄alkoxy)phenyl.
 4. A compound as claimed in claim 1 wherein R³ ishydrogen.
 5. A compound as claimed in claim 1 wherein R⁴ is ethyl.
 6. Acompound as claimed in claim 1 wherein R⁵ is hydrogen, halo, hydroxy,nitro, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃ or OCF₃.
 7. A compound asclaimed in claim 1 wherein R⁶ is C₁₋₄ alkyl and wherein the S(O)₂R⁶group of formula (I) is para disposed to the remainder of the structureof formula (I).
 8. A process for the preparation of a compound asclaimed in claim 1, the process comprising: a) reductive amination of acompound of formula (II) or (IIa):

with a compound of formula (III):

in the presence of NaBH(OAc)₃ (wherein Ac is C(O)CH₃) and acetic acid,in a suitable solvent at room temperature; or, b) coupling a compound offormula (IV) or (IVa):

with a compound of formula (V):

in the presence of a suitable coupling agent, in the presence of asuitable base, in a suitable solvent and at room temperature.
 9. Apharmaceutical composition which comprises a compound as claimed inclaim 1, or a pharmaceutically acceptable salt thereof or solvatethereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.10-11. (Cancelled)
 12. A method of treating a CCR5 mediated diseasestate comprising administering to a patient in need of such treatment aneffective amount of a compound as claimed in claim
 1. 13. The method ofclaim 8 wherein the temperature during step b) is from 10° C. to 30° C.